32.1 Structure and Physiology of the immune system

Question 1

What are the primary lymphoid organs?

Answer 1

The site of lymphocyte production, not activation.

Question 2

What is the PLO for T-cells?

Answer 2

Bone marrow, then thymus.

Question 3

What is the PLO for B-cells?

Answer 3

Bone marrow

Question 4

Describe the structure of the thymus

Answer 4

Made up of several lobules
Each lobule is split into two regions = dense cortical (outer) and less dense medullary (central) regions
Wrapped in a capsule

Question 5

What is the function of the epithelial cells in the cortex of the thymus?

Answer 5

Releases signals to thymic progenitor cells which activates the Notch1 receptor to instruct the precursor to become committed to a T cell lineage rather than B cell

Question 6

Which cell expresses the MHC molecules during positive selection?

Answer 6

cTEC (cortical thymic epithelial cells)

Question 7

Which cell types are found in the cortex of the thymus?

Answer 7

Immature thymocytes closely associated to branched cortical epithelial cells (thymic stroma analogous to stromal cells in bone marrow) and macrophages which kill apoptotic thymocytes

Question 8

Which cell types are found in the medulla of the thymus?

Answer 8

Mature thymocytes and medullar epithelial cells
Macrophages
Dendritic cells
Hassans corpsucles - cell degradation

Question 9

What is the positive selection of T cells in the PLO?

Answer 9

The rescue of double positive thymocytes from programmed cell death and their maturation into CD4 or CD8 single positive cells based on the avidity of the beta chain.

Question 10

Describe the process of thymocyte (T cell progenitor) differentiation.

Answer 10

• T cells progenitors in the outer thymus begin as double-negative T cells that express neither CD4 or CD8
• During this time, VDJ recombination occurs
  
  • First the beta chain is rearranged (using VDJ recombinase).
  • While the beta chain is being rearranged, it is complexed with an invariant pT-alpha chain. Ligation of the pre-TCR terminates beta rearrangement and alpha rearrangement can occur. This occurs when the the pre-TCR undergoes auto-dimerisation (it is its own ligand), signalling that it is somewhat functional.
  • Then the alpha chain is rearranged (since the beta chain locus is inaccessible and the alpha chain locus is accessible to the VDJ recombinase).
• This induces the T cell to then become double positive, expressing both CD4 and CD8
• The T cell proliferates ready for positive selection
• Positive selection leads to only either CD4 or only CD8 being expressed

Question 11

What is the difference in the T cells found in the cortex and the medulla of the thymus?

Answer 11

Cortical T cells = proliferating immature cells that are becoming committed to a T cell lineage
Medullary T cells = immature T cells undergoing thymic selection

Question 12

What are the three types of cell that are important in T cell development and central tolerance?

Answer 12

• Cortical thymic epithelial cells (cTECs) -> Positive selection
• Medullary thymic epithelial cells (mTECs) + Dendritic cells -> Negative selection

This means that cells travelling from the outer cortex to inner medulla first undergo postive selection and then negative selection.

Question 13

In what order do positive and negative selection of lymphocytes occur?

Answer 13

Positive then negative

Question 14

How does positive selection of T cells occur?

Answer 14

• Cortical thymic epithelial cells (cTECs) have a stellate morphology and form a 3-dimensional network with no basement membrane
• This means there is interaction between developing T cells and the epithelial cells
• The cTECs constitutively express both MHC class I and class II
• If the TCR binds more to the MHC class I than class II, then the CD8 receptor is stabilised and the CD4 receptor is lost
• If the TCR binds more to the MHC class II than class I, then the CD4 receptor is stabilised and the CD8 receptor is lost
• If there is insufficient affinity, then the cell dies by apoptosis

Question 15

What are the consequences of positive selection of T cells?

Answer 15

• Rescues the T cells from apoptosis
• Imposes MHC-restricted antigen recognition on the emerging T cell repertoire
• Lineage commitment to either the CD4+ helper T cell lineage or to the lineage of CD8+ CTL

Question 16

How is positive and negative selection distinguished if both processes involve binding self peptides: self MHC?

Answer 16

Depends on the threshold of avidity (affinity hypothesis)
Low affinity interactions rescues the cells from death = positive selection
High affinity interactions induces apoptosis = negative selection

Question 17

What is the purpose of negative selection of T cells?

Answer 17

It prevents self-reactive T cells from surviving and leaving the thymus.

Question 18

How are T cells prevented from leaving the thymus before negative selection occurs?

Answer 18

• Capillaries draining the cortex are impermeable to plasma proteins or the passage of cells
• Vessels in the cortex are composed of non-fenestrated endothelium and a thick basal lamina
• A reticular sheath surrounds the vessels composed of reticular cells and macrophages

Question 19

Where does negative selection occur?

Answer 19

In the medulla (part in the cortex by cTEC) mediated by medullary epithelial cells (mTEC) and dendritic cells

Question 20

What are the major surface molecules of T cells?

Answer 20

T cell Ag receptor, CD3, CD4, CD8, adhesion molecules, CK + Chemokine receptors (e.g. IL-2R).

Question 21

What are the major surface molecules of B-cells?

Answer 21

Surface Ig, MHC class II, adhesion molecules, Chemokine and CK receptors.

Question 22

What are the individual co-stimulatory molecules?

Answer 22

CD40L, CD28, and other signalling molecules (e.g. PD1, CTLA4, Fas ligand and Fas (CD95))

Question 23

List the major surface molecules on B cells and what they bind to (6 types)

Answer 23

BCR (antibody bound) binds to antigen
CD20 (defines B cell)
CD40 - costimuatory molecule that binds to CD40L on T helper cells to become activated
Chemokine receptors
Toll like receptors (TLRs)
CD80 - binds to CD28 on T cells to activate them

Question 24

List the negative regulators of T cell activation. What do they bind to?

Answer 24

EXPRESSED BY T CELLS:
PD-1 (programmed death-1)
CTLA4 (CD152) : Binds to same costimulatory ligands as CD28 (CD80 and CD86) to inhibit T cell activation

Question 25

What are the major surface molecules on T cells and what do they bind to? (6 types)

Answer 25

TCR - binds to antigen:MHC complex
CD4 or CD8 - stabilises MHC/peptide:TCR complex
CD3 - T cell co receptor that mediates signal transduction
CD28 - ESSENTIAL co stimulatory molecule needed for T cell activaton, binds to CD80 (aka B7) on antigen presenting cells
Adhesion molecules (L-selectin,
Chemokine receptors (IL-2R) - binds to cytokines needed for activation

Question 26

What is expressed on T helper cells that is not expressed on T effector cells?

Answer 26

CD40L on follicular T helper cells

Question 27

What is the role of Fas (CD95) and Fas ligand? Which cells express it?

Answer 27

Effector T cells express Fas which binds to Fas ligand (CD178) to induce apoptosis once an infection has been cleared

Question 28

Which chemokines attract B cells to follicles?

Answer 28

CXCL13

Question 29

Which chemokines attract T cells to follicles?

Answer 29

CCL21 and CCL19

Question 30

Which family of ligands does CD28 bind to?

Answer 30

B7 family

Question 31

What are some other signalling molecules on lymphocytes that you need to know?

Answer 31

• PD1 -> Suppresses T cell inflammatory activity by promoting apoptosis (programmed cell death) of antigen-specific T-cells in lymph nodes and it reduces apoptosis in regulatory T cells.
• CTLA-4 -> Suppresses T cell inflammatory activity. When CTLA-4 is bound to another protein called B7, it helps keep T cells from killing other cells, including cancer cells.
• Fas and Fas ligand -> Involved in apoptosis

Question 32

How does the location of the secondary lymphoid organs contribute to their function?

Answer 32

They are the origin of the immune responses. Hence their location is sited to monitor pathogen entry.

Question 33

What are the secondary lymphoid organs?

Answer 33

Lymph nodes, Spleen, Peyer’s patches.

Question 34

What do the lymph nodes monitor?

Answer 34

Solid tissues

Question 35

What does the spleen monitor?

Answer 35

Blood

Question 36

What do Peyer’s patches and equivalent (MALT/ GALT) monitor?

Answer 36

mucosae

Question 37

Describe the path taken by circulating lymphocytes

Answer 37

Lymph node
Efferent lymphatic vessel
Venous circulation
Arterial circulation (spleen)
High endothelial venules
Lymph node

Question 38

Describe the structure of secondary lymphoid organs

Answer 38

Outer capsule surrounding them
Follicles interspersed in the organ adjacent to T cell zones
Lymph received through afferent lymphatic vessels which drain all tissues accumulates in the subcapsular sinus and seeps into deep structures
Paracortex contains high endothelial venules
Arteries and veins also supply lymph nodes

Question 39

Describe the structure of the spleen. How is this different to lymph nodes?

Answer 39

Contains red pullp and white pulp
White pulp contains B cell follicles and T cell zones
NOT SUPPLIED BY AFFERENT LYMPHATIC VESSELS
Recieve input via splenic artery and this is distributed to the arterioles

Question 40

What are High endothelial venules?

Answer 40

Site of lymphocyte exit from blood.

Question 41

Describe the concept of primary follicles, secondary follicles and germinal centres.

Answer 41

These are all structures within secondary lymphoid organs (lymph nodes and spleen):

• Primary follicles contain naive B lymphocytes
• Secondary follicles are those that have developed a germinal centre
• Germinal centres are the sites of actived B cell proliferation and somatic hypermutation

In other words, B cells in primary follicles are activated during the immune response and then form germinal centres. The follicles are then known as secondary follicles.

Question 42

What body compartments do each of the secondary lymphoid organs sample?

Answer 42

• Spleen is highly vascularised, so it samples the blood
• Peyer’s patches sample the gut
• Lymph nodes drain tissue fluid from interstitial tissues

Question 43

Describe the structure and function of the spleen.

Answer 43

It is made of two parts:

• Red pulp -> Contains a store of erythrocytes in case of haemorrhage, No immunological function
• White pulp -> Wraps around arterioles (periarterial lymphatic sheath) and contains:
  
  • Naive T cells freely arranged
  • Primary follicles containing naive B cells

Question 44

Describe the structure and function of lymph nodes.

Answer 44

• Afferent lymphatics bring tissue fluid in
• Tissue fluid accumulates in the marginal sinus (just inside the capsule), then percolates into the medulla, from which it exits via the efferent lymphatic
• Cords in the medulla are made up of plasma cells that can secrete IgM antibodies (they are the source of the IgM that is produced early in the primary immune response)
• The IgM exits at the efferent lymphatic and enters the blood at the subclavian vein
• The paracortex contains naive T cells
• The primary follicles contain naive B cells

Question 45

What is the structure of Peyer’s patches?

Answer 45

small clusters of lymphatic tissue within the lamina propria of the small intestine extending to the submucosa of the ileum.
*They are NOT surrounded by a connective tissue capsule.